Amide dendrimer compositions

ABSTRACT

Amide compounds, amide polymers, compositions including amide compounds and amide polymers may be used to bind target ions, such as phosphorous-containing compounds in the gastrointestinal tract of animals. In some cases, amide compounds and amide polymers may include a core derived from an amide polyol and an organic polyacid or ester.

FIELD OF THE INVENTION

This invention relates to amide polymers for binding compounds or ions,and more specifically relates to pharmaceutically acceptablecompositions, amide dendrimers, amide polymers or residues thereof forbinding target ions.

BACKGROUND OF THE INVENTION

Hyperphosphatemia frequently accompanies diseases associated withinadequate renal function such as end stage renal disease (ESRD),hyperparathyroidism, and certain other medical conditions. Thecondition, especially if present over extended periods of time, leads tosevere abnormalities in calcium and phosphorus metabolism and can bemanifested by aberrant calcification in joints, lungs, and eyes.

Therapeutic efforts to reduce serum phosphate include dialysis,reduction in dietary phosphate, and oral administration of insolublephosphate binders to reduce gastrointestinal absorption. Many suchtreatments have a variety of unwanted side effects and/or have less thanoptimal phosphate binding properties, including potency and efficacy.Accordingly, there is a need for compositions and treatments with goodphosphate-binding properties and good side effect profiles.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention relates to amide compounds, amidepolymers and/or compositions comprising or derived from the same orresidues thereof. The amide compounds (amide dendrimers) comprise amidepolyol cores (formed, for example, from an organic polyacid or esterthereof substituted at one or more of the acid hydroxyl groups with oneor more amine polyols). The amide compounds can be crosslinked to formamide polymers. Compositions can comprise one or more amide compounds orresidues thereof and/or amide polymers or residues thereof. Severalembodiments of the invention, including this aspect of the invention,are described in further detail as follows. Generally, each of theseembodiments can be used in various and specific combinations, and withother aspects and embodiments for a variety of pharmaceutical andtherapeutic uses unless otherwise stated herein.

In another aspect, the present invention relates to amine polyethercompounds, amine polyether polymers and/or compositions comprising orderived from the same or residues thereof. The amine polyether compounds(amine polyether dendrimers) comprise amine polyol cores. The aminepolyether compounds may be crosslinked to form amine

In addition to the amide compounds, amide polymers, amine polyethercompounds and amine polyether polymers of the present invention asdescribed herein, other forms of the amide compounds, amide polymers,amine polyether compounds and amine polyether polymers are within thescope of the invention including pharmaceutically acceptable salts,solvates, hydrates, prodrugs, polymorphs, clathrates, and isotopicvariants and mixtures thereof of the amide compounds, amide polymers,amine polyether compounds and/or amine polyether polymers.

In addition, amide compounds, amide polymers, amine polyether compoundsand amine polyether polymers of the invention may have optical centers,chiral centers or double bonds and the amide compounds, amide polymers,amine polyether compounds and amine polyether polymers of the presentinvention include all of the isomeric forms of these compounds andpolymers, including optically pure forms, racemates, diastereomers,enantiomers, tautomers and/or mixtures thereof.

In a first embodiment, the invention is, consists essentially of, orcomprises an amide compound or an amide polymer that comprises at leastone amide compound or residue thereof, where the amide compound isrepresented by Formula I, as follows:

wherein n independently represents an integer from 0-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R independently represents ahydrogen radical, a hydroxyl radical, —OR₃, —R₂OH, —R₂OR₃, orC(O)N(R₁)₂; R₁ independently represents a hydrogen radical, a hydroxylradical, —OR₃, or a branched or unbranched substituted C₁-C₁₀, such as aC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, alkyl radical, wherein one ormore carbon atoms of the alkyl radical may be partially or fullysubstituted with —OH and/or —OR₃ groups, for example a C₃-C₈ branchedalkyl radical having

wherein p, q and r independently represent an integer from 0-2, forexample, 0, 1 or 2; R₄ independently represents

wherein m independently represents an integer from 1-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R₅ independently represents ahydrogen radical; a substituted or un-substituted alkyl radical; asubstituted or un-substituted aryl radical; or R₅ and a neighboring R₅together represent a link or links comprising a residue of acrosslinking agent, for example epichlorohydrin or other crosslinkingagents, a substituted or un-substituted alicyclic radical, a substitutedor un-substituted aromatic radical, or a substituted or un-substitutedheterocyclic radical; or R₅ represents a link with another compound or aresidue thereof.

In another aspect, the invention provides methods of treating an animal,including a human. The method generally involves administering atherapeutically effective amount of an amide polymer described herein.

Another aspect of the invention is a pharmaceutical compositioncomprising one or more amide polymers or amine polyether polymers of thepresent invention with at least

In some embodiments, the invention comprises an amide polymer or anamine polyether polymer that comprises an amide dendrimer or residuethereof or an amine polyether dendrimer or residue thereof, where thedendrimer comprises an amide polyol core or an amine polyol core andbranches emanating from the core, where the branches are based onsubstituted or un-substituted α, β unsaturated nitrile units. Thebranches may be formed using a reiterative reaction sequence thatincludes a Michael addition of the substituted or un-substituted α, βunsaturated nitrile and a reduction of the nitrile group to a primaryamine.

In yet another aspect, the amide polymers, amine polyether polymersand/or pharmaceutical compositions are useful for removing othersolutes, such as chloride, bicarbonate, and/or oxalate containingcompounds or ions. Amide polymers and amine polyether polymers removingoxalate compounds or ions find use in the treatment of oxalate imbalancedisorders. Amide polymers and amine polyether polymers removing chloridecompounds or ions find use in treating acidosis, for example. In someembodiments, the amide polymers and amine polyether polymers are usefulfor removing bile acids and related compounds.

The invention further provides compositions containing any of the aboveamide polymers or amine polyether polymers where the amide polymer oramine polyether polymers is in the form of particles and where theparticles are encased in one or more shells.

In another aspect, the invention provides pharmaceutical compositions.In some embodiments, the pharmaceutical composition contains an amidepolymer or an amine polyether polymers of the invention and apharmaceutically acceptable excipient. In some embodiments, thecomposition is a liquid formulation in which the amide polymer or theamine polyether polymer is dispersed in a liquid vehicle, such as water,and suitable excipients. In some embodiments, the invention provides apharmaceutical composition comprising an amide polymer or an aminepolyether polymer for binding a target compound or ion, and one or moresuitable pharmaceutical excipients, where the composition is in the formof a tablet, sachet, slurry, food formulation, troche, capsule, elixir,suspension, syrup,

In some of the compositions of the invention, the excipients are chosenfrom the group consisting of sweetening agents, binders, lubricants, anddisintegrants. Optionally, the amide polymer is present as particles ofless than about 80 μm mean diameter. In some of these embodiments, thesweetening agent is selected from the group consisting of sucrose,mannitol, xylitol, maltodextrin, fructose, and sorbitol, andcombinations thereof.

In some embodiments, the invention provides amide polymers orcompositions that comprise an amide dendrimer or residue thereof, wherethe amide dendrimer is formed from a core that comprises an amide polyolthat is substituted with one or more amine groups represented by thefollowing Formula II:

wherein p, q and r independently represent an integer from 0-2, forexample, 0, 1 or 2; R₄ independently represents

wherein m independently represents an integer from 1-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R₅ independently represents ahydrogen radical; a substituted or un-substituted alkyl radical; asubstituted or un-substituted aryl radical; or R₅ and a neighboring R₅together represent a link or links comprising a residue of acrosslinking agent, for example epichlorohydrin or other crosslinkingagents, a substituted or un-substituted alicyclic radical, a substitutedor un-substituted aromatic radical, or a substituted or un-substitutedheterocyclic radical; or R₅ represents a link with another compound or aresidue thereof.

In still other embodiments, a polymer network may include two or morepolymers, where at least one of the polymers is an amide polymer derivedfrom an amide compound represented by Formula I, that may be linked toform a polymer network. For example, in some embodiments a polymernetwork may comprise a residue of two or more amide polyols, a residueof one or more substituted or un-substituted α, β unsaturated nitrilegroups and a residue of one or more crosslinking agents. In someembodiments, the polymer network may be formed where all orsubstantially all of the polymers may be amide polymers that are derivedfrom amide compounds represented by Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides amide compounds, amidepolymers, compositions and methods of using amide polymers orcompositions comprising an amide polymer or amide compound or residuethereof, where the amide compound is represented by Formula I. In someembodiments, the compositions may comprise amide polymers that may bederived from two or more of the amide compounds described herein.

In addition, some embodiments may include multiple amide compounds orresidues thereof or amine polyether compounds or residues thereof thatrepeat in a copolymer or polymer. Such polymers may include one or moreadditional compounds that may be included in a polymer backbone or aspendant groups either individually or as repeating groups, and that mayprovide separation between the individual amide polymers or aminepolyether polymers.

As used herein, unless otherwise stated, the term “derived from” isunderstood to mean: produced or obtained from another substance bychemical reaction, especially directly derived from the reactants, forexample an amide compound may be derived from the reaction of an amidepolyol and a substituted or un-substituted α, β unsaturated nitrile thatis subsequently hydrogenated to form an amide compound having one ormore generations of dendritic branching. Additionally, an amide compoundthat is reacted with a linking agent,

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula I, as follows:

wherein n independently represents an integer from 0-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R independently represents ahydrogen radical, a hydroxyl radical, —OR₃, —R₂OH, —R₂OR₃, orC(O)N(R₁)₂; R₁ independently represents a hydrogen radical, a hydroxylradical, —OR₃, or a branched or unbranched substituted C₁-C₁₀, such as aC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, alkyl radical, wherein one ormore carbon atoms of the alkyl radical may be partially or fullysubstituted with —OH and/or —OR₃ groups, for example a C₃-C₈ branchedalkyl radical having more than one substitution, such as C₄-C₇ branchedalkyl substituted with 2 or more —OH and/or —OR₃ groups, or C₃ branchedalkyl substituted with 3 or more —OH and/or —OR₃ groups; R₂independently represents a substituted or unsubstituted, branched orunbranched alkyl radical; and R₃ is independently represented by thefollowing Formula II:

wherein p, q and r independently represent an integer from 0-2, such as0, 1 or 2; R₄ independently represents

wherein m independently represents an integer from 1-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R₅ independently represents ahydrogen radical; a substituted or un-substituted alkyl radical; asubstituted or un-substituted aryl radical; or R₅ and a neighboring R₅together represent a link or links comprising a residue of acrosslinking agent, for example epichlorohydrin or other crosslinkingagents, a substituted or un-substituted alicyclic radical, a substitutedor un-substituted aromatic radical, or a substituted or un-substitutedheterocyclic radical; or R₅ represents a link with another compound or aresidue thereof.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula I, wherein R₁ independentlyrepresents a branched or unbranched substituted C₁-C₁₀ alkyl radicalthat is partially or fully substituted with 1-20, for example 2-10, 2-6,2-4, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 or 20, —OH and/or OR₃ groups.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula I, wherein at least one Rcomprises —OR₃.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula I, and where R₃independently represents a group represented by the following FormulaIIa:

where p, r, R₄ and R₅ are as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula I, where R₃ independentlyrepresents a group represented by the following Formula IIb:

where R₄ and R₅ are as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula III, as follows:

where R₃ independently represents a group represented by Formula II,Formula IIa, or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula IV, as follows:

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula V, as follows:

wherein R₃ independently represents a group represented by Formula II,Formula IIa, or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula VI, as follows:

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide polymer comprises at least one amide compound or residuethereof, where the amide compound comprises a substituted amide polyolor residue thereof. The amide polyol may comprise a residue of asubstituted or unsubstituted organic polyacid or ester thereof and aresidue of a substituted or unsubstituted amine polyol. The amide polyolmay be substituted with one or more groups represented by Formula II,Formula IIa, or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound comprises a substituted amide polyol having one ormore units, for example 2-40 units, such as 3-30, 4-25, 5-20, 6-15 or8-12 units or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, or 39 units represented by the group comprising thefollowing Formula VII:

wherein p, q and r independently represent an integer from 0-2, forexample, 0, 1 or 2; R₄ independently represents

wherein m independently represents an integer from 1-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R₅ independently represents ahydrogen radical; a substituted or un-substituted alkyl radical; asubstituted or un-substituted aryl radical; or R₅ and a neighboring R₅together represent a link or links comprising a residue of acrosslinking agent, for example epichlorohydrin or other crosslinkingagents, a substituted or un-substituted alicyclic radical, a substitutedor un-substituted aromatic radical, or a substituted or un-substitutedheterocyclic radical; or R₅ represents a link with another compound or aresidue thereof.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide polymer comprises an amide dendrimer or residue thereof, thedendrimer comprising a core that is a residue of one or more substitutedor un-substituted organic polyacids or esters thereof and a residue ofone or more amine polyols and the dendrimer further comprising a residueof one or more substituted or un-substituted α, β unsaturated nitriles.

In some embodiments, dendrimers of the present invention may be formedfrom any suitable reaction scheme. Dendrimers are macromolecularcompounds that comprise a core that includes functional groups anddendritic branches that may be formed through a series of iterativereaction sequences starting with the functional groups on the core toform a branched macromolecule. In some embodiments the reactivefunctional groups comprise hydroxyl groups and/or amine groups. Thefunctional groups will have functionalities that are dependent on thetype of group. For example, hydroxyl groups have a functionality of one,while primary amines generally have a functionality of 2, though theymay be quaternized. In some embodiments, an amide polymer comprises adendrimer or residue thereof. In some embodiments, the dendrimer maycomprise an amide polyol core that is a

In some embodiments, amide dendrimers of the present invention areprepared by reaction of an amide polyol core that is reacted withsubstituted or un-substituted α, β unsaturated nitriles and subsequentlyreduced, resulting in dendritic branching. An amide polyol core may beformed by reaction of an amine polyol with an organic polyacid or esterthereof to form the amide polyol. An example of an amide polyol formedby this reaction is set forth in Scheme IA, using tartaric acid as thepolyacid and 2-aminopropane-1,2,3-triol as the polyol:

The amide polyol may then be reacted by Michael addition of asubstituted or un-substituted α, β unsaturated nitrile to one or more ofthe hydroxyl groups on the amide polyol core to replace the hydrogen ofone or more hydroxyl groups with one or more alkyl cyanide groups,resulting in an ether linkage to the core via the oxygen atom of thehydroxyl groups. The nitriles of the alkyl cyanide groups of theresulting compound are then chemically reduced, for example viahydrogenation, to form the corresponding primary amines. The Michaeladdition and subsequent reduction may be performed on the primary aminesyielding branched tertiary or secondary amines terminating in primaryamines. Subsequent Michael additions and reductions may be repeated oneor more times to provide the branched structure characteristic ofdendrimers. A schematic of this process is provided below in Scheme IB,using the amide polyol from Scheme IA as the polyol and acrylonitrile asthe α, β unsaturated nitrile:

In some embodiments, each iteration of Michael addition and subsequentreduction may be considered one generation. Thus, for some embodiments,a compound having one generation of dendritic branching may haveundergone one iteration of Michael addition and reduction, compoundshaving two generations of dendritic branching may have undergone twoiterations of Michael addition and reduction, compounds having threegenerations of dendritic branching may have undergone three iterationsof Michael addition

In some embodiments, a method of making an amide polymer comprisesreacting an organic polyacid or an ester thereof with an amine polyol toform an amide polyol core, reacting the amide polyol core with asubstituted or un-substituted α, β unsaturated nitrile using a Michaeladdition reaction to form a polyether, reducing at least one nitrilegroup on the polyether to form a primary amine, repeating the Michaeladdition and reduction on the at least one primary amine one or moretimes to form an amide dendrimer; and crosslinking the amide dendrimerwith a crosslinking agent to form an amide polymer.

In some embodiments, the present invention is a polymer network, apharmaceutical composition (comprising or derived from polymer networkor a residue thereof) or a method of using the same in a therapeuticallyeffective amount to remove a compound or ion, such as aphosphorous-containing compound or a phosphorous-containing ion (e.g.phosphate), from the gastrointestinal tract of an animal where the apolymer network comprises two or more amide polymers or residuesthereof. The polymer network may comprise a residue of two or moresubstituted or un-substituted amide polyols, a residue of one or moresubstituted or un-substituted α, β unsaturated nitrile groups and aresidue of one or more crosslinking or other linking agents. In someembodiments, the polymer network comprises residues of two or morepolyethers, where the polyethers comprise a residue of one or more amidepolyols and a residue of one or more substituted or un-substituted α, βunsaturated nitrile groups, and where the network also comprises aresidue of one or more crosslinking agents. In some embodiments, thepolymer network may include one or more amide dendrimers or residuesthereof.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide polymer comprises two or more amide dendrimers or residuesthereof represented by Formula V, wherein R₃ independently represents agroup represented by Formula II, Formula IIa, or Formula IIb as definedabove.

In some embodiments, the present invention is an amide polymer(comprising or derived from an amide compound or a residue thereof), apharmaceutical composition (comprising or derived from said amidepolymer or a residue thereof), a polymer network (comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal, theamide polymer, polymer network or composition having a plurality ofunits represented by the following Formula VIII:

wherein R₄ independently represents

wherein m independently represents an integer from 1-20, for example,1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20; R₅ independently represents ahydrogen radical; a substituted or un-substituted alkyl radical; asubstituted or un-substituted aryl radical; or R₅ and a neighboring R₅together represent a link or links comprising a residue of acrosslinking agent, for example epichlorohydrin or other crosslinkingagents, a substituted or un-substituted alicyclic radical, a substitutedor un-substituted aromatic radical, or a substituted or un-substitutedheterocyclic radical; or R₅ represents a link with another compound or aresidue thereof;

and a plurality of units represented by the following Formula IX:

In some embodiments, the invention is a method for reducing bloodphosphate levels by 5-100% in a patient in need thereof, the methodcomprising administering a therapeutically effective amount of an amidepolymer, amine polyether polymer or composition to the patient, wherethe amide polymer or composition comprises an amide compound or residuethereof, the amide compound represented by Formula I. In someembodiments, the invention is a method for reducing urinary phosphorousby 5-100% in a patient in need thereof, the method comprisingadministering a therapeutically effective amount of an amide polymer,amine polyether polymer or composition to the patient, where the amidepolymer or composition comprises an amide compound or residue thereof,the amide compound represented by Formula I or a residue thereof.

In some embodiments, the present invention is an amine polyethercompound, an amine polyether polymer (comprising or derived from saidamine polyether compound or a residue thereof), a pharmaceuticalcomposition (comprising or derived from said amine polyether compound ora residue thereof or comprising or derived from said amine polyetherpolymer or a residue thereof) or a method of using the same in atherapeutically effective amount to remove a compound or ion, such as aphosphorous-containing compound or a phosphorous-containing ion (e.g.phosphate), from the gastrointestinal tract of an animal where the aminepolyether compound is represented by Formula X, as follows:

wherein R₈ independently represents a hydrogen radical or —OR₉ and R₉independently represents a hydrogen radical or a group represented byFormula II, Formula IIa or Formula IIb as defined above.

In some embodiments, amine polyol compounds that may be used to form theamide polyol cores for, or in the preparation of amide compounds, amidepolymers, polymer networks and compositions according to someembodiments of the invention include any amine polyols and in someembodiments may be represented by the following general molecularformula:

N_(a)R₆(OH)_(c)

where a independently represents an integer from 1 to 6, for example 1,2, 3, 4, 5 or 6; c independently represents an integer from 1-10, forexample 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and R₆ independently represents abranched or unbranched, substituted or unsubstituted C₁ to C₁₀ alkylgroup.

In some embodiments, examples of some suitable amine polyols includeamine-substituted polyhydric alcohols. Examples of some polyhydricalcohols that may be amine substituted to form suitable amine polyolsinclude 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol,1,6-cyclohexanedimethanol, 2-methyl-1,3-propanediol,2-methyl-2-ethyl-1,3-propanediol, 2-ethyl-2-butyl-1,3-propanediol,neopentyl glycol, dimethylolpropane, 1,1-dimethylolcyclohexane,glycerol, trimethylolethane, trimethylolpropane, diglycerol,ditrimethylolethane, ditrimethylolpropane, pentaerythritol,dipentaerythritol and sugar alcohols.

Sugar alcohols that may be amine substituted to form suitable aminepolyols include sugar alcohols derived from aldoses and ketosesincluding those derived from monoses, dioses, trioses, tetroses,pentoses, hexoses, heptoses, octoses and nonoses. The aldoses andketoses from which the sugar alcohols are derived may be fully orpartially hydrogenated, and may be substituted, including replacement ofone or more hydroxyl groups on the aldose or ketose with one or morehydrogen groups to form the corresponding deoxyaldose or deoxyketose,provided that at least two alcohol groups remain. Specific examples ofaldoses and ketoses from which suitable sugar alcohols may be derivedinclude: erythrose, threose, ribose, deoxyribose, arabinose, xylose,lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose,talose, ribulose, xylulose, fructose, psicose, tagatose, mannoheptulose,sedoheptulose, sorbose, pentaerythrose, octolose, sialose or a partiallyor fully hydrogenated derivatives thereof, or a combinations thereof.Non-limiting examples of some suitable sugar alcohols that may be aminesubstituted include sorbitol, mannitol, xylitol, erythritol, galactitol,dulcitol, arabitol, threitol, arabinitol, ribitol, and rhamnitol.

In some embodiments, suitable amine polyol compounds that may be used toform the cores for, or in the preparation of amide compounds, amidepolymers, polymer networks and compositions according to someembodiments of the invention include:

In some embodiments, the invention includes amine polyether compoundsthat may be formed from any of the amine polyols described herein. Insome embodiments, the amine polyether compounds are formed via Michaeladdition and reduction on the hydroxyl groups and/or amine groups of theamine polyols similar to the reaction described above with respect tothe amide polyols. The resulting amine polyether compounds may becrosslinked to form amine polyether polymers. The amine polyethercompounds and amine polyether polymers may be used in pharmaceuticalcompositions, polymer networks and methods of treatment as describedherein with respect to the amide polymers and compositions.

In some embodiments, organic polyacids and/or esters thereof may be usedto form the cores for, or in the preparation of, amide compounds, amidepolymers, polymer networks and compositions according to someembodiments of the invention. Esters of all of the organic polyacids maybe used instead of, or in conjunction with, the organic polyacids,including polyacids that are partially and fully esterified. Examples ofthe polyacids include any organic polyacids, including diacids,triacids, tetracids, pentacids and hexacids. Examples of some polyacidsthat may be used include substituted or un-substituted

In some embodiments, suitable organic polyacids that may be used to formthe cores for, or in the preparation of, amide compounds, amidepolymers, polymer networks and compositions according to someembodiments of the invention include aldaric acids having the followinggeneral formula:

HOOC—(CHOH)_(w)—COOH

wherein w represents an integer from 1 to 20, for example, 1-15, 1-2,3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20. Additional examples of suitable aldaric acidsinclude diacids formed from any of the sugar alcohols as mentionedabove. In some embodiments, one or more of the non-acid hydroxyl groupsof the aldaric acids may be replaced with an amine group.

In some embodiments, suitable organic polyacids may be cyclic polyacidssuch as aromatic, alicyclic or heterocyclic polyacids having a 3, 4, 5or 6 membered ring or rings that are partially or fully substituted withcarboxylic acid groups. For example, a 3-membered polyacid ring may have2, or 3 carboxylic acid groups, a 6-membered polyacid ring may have 2,3, 4, 5, or 6 carboxylic acid groups and a naphthalene group may have 2,3, 4, 5, 6, 7 or 8 carboxylic acid groups. The heterocyclic organicpolyacids may be aromatic or non-aromatic and may have up to fourheteroatoms selected from N, O and S and combinations thereof. Thecyclic polyacids may additionally have non-acid substitutions on therings including, for example, —OH groups.

Examples of some aromatic, alicyclic and heterocyclic groups that may besubstituted with at least 2 carboxylic acids to form suitable organicpolyacids include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,piperidinyl, piperizinyl, thiazolidinyl, imidazolidinyl, pyranyl,tetrahydrofuranyl, oxanyl, benzyl, pyridinyl, imidazolyl, pyrazolyl,thiazolyl, oxazolyl, pyrimidinyl, dioxanyl, quinizolinyl, indolinyl,benzothiazolyl, benzooxazolyl, pyrazinyl, furanyl, thenyl, naphthalenyland the like.

Non-limiting examples of some suitable cyclic polyacids include:cyclohexane-1,2-dicarboxylic acid, cyclohexane-1,3-dicarboxylic acid,cyclohexane-1,4-dicarboxylic

Examples of some suitable organic polyacids include:

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XI, as follows:

wherein R₁ is as defined above for Formula I, and R₇ independentlyrepresents H or a group represented by Formula II, Formula IIa, orFormula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XII, as follows:

wherein R and R₁ are as defined above for Formula I, and R₃independently represents a group represented by Formula II, Formula IIa,or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XIII, as follows:

wherein R and R₁ are as defined above for Formula I, and R₃independently represents a group represented by Formula II, Formula IIa,or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XIV, as follows:

wherein R and R₁ are as defined above for Formula I, and R₃independently represents a group represented by Formula II, Formula IIa,or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XV, as follows:

wherein R and R₁ are as defined above for Formula I, and R₃independently represents a group represented by Formula II, Formula IIa,or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XVI, as follows:

wherein R₁ is as defined above for Formula I, and R₃ independentlyrepresents a group represented by Formula II, Formula IIa, or FormulaIIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XVII, as follows:

wherein R and R₁ are as defined above for Formula I, and R₃independently represents a group represented by Formula II, Formula IIa,or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XVIII, as follows:

wherein R is as defined above for Formula I and R₃ independentlyrepresents a group represented by Formula II, Formula IIa, or FormulaIIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XIX, as follows:

wherein R₁ is as defined above for Formula I and R₃ independentlyrepresents a group represented by Formula II, Formula IIa, or FormulaIIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a

wherein R₃ independently represents a group represented by Formula II,Formula IIa, or Formula IIb as defined above.

In some embodiments, the present invention is an amide compound, anamide polymer (comprising or derived from said amide compound or aresidue thereof), a pharmaceutical composition (comprising or derivedfrom said amide compound or a residue thereof or comprising or derivedfrom said amide polymer or a residue thereof) or a method of using thesame in a therapeutically effective amount to remove a compound or ion,such as a phosphorous-containing compound or a phosphorous-containingion (e.g. phosphate), from the gastrointestinal tract of an animal wherethe amide compound is represented by Formula XXI, as follows:

wherein R₃ independently represents a group represented by Formula II,Formula IIa, or Formula IIb as defined above.

In some embodiments, the invention is a method of treating a phosphateimbalance disorder such as hyperphosphatemia comprising administering atherapeutically effective amount of an amide polymer or composition to apatient in need thereof. In some embodiments, the amide polymer orcomposition comprises an amide compound or residue thereof according toFormula I.

In some embodiments, a method of treating a phosphate imbalance disordersuch as hyperphosphatemia comprises administering a therapeuticallyeffective amount of an amine polyether polymer, an amide polymer orcomposition to a patient in need thereof, where the amine polyetherpolymer or the amide polymer or composition comprises an amine polyethercompound or residue thereof or an amide compound or residue thereofrepresented by at least one of Formulas III-VI, X-XXI or where the amidepolymer or composition comprises a plurality of units according toFormula VII, or a plurality of units according to Formulas VIII and IX.

In some embodiments, the amide compound is a mixture of more than oneamine polyether compound or amide compound, for example 2-20 such as 2,3, 4, 5, 6, 7, 8, 9 or 10 amine polyether compounds or amide compoundsrepresented by Formulas I, III-VI or X-XXI. In some embodiments, themixture predominantly comprises an amine polyether compound or an amidecompound represented by one of Formulas I, III, V or X-XXI where q, rand p are independently 0 or 2. For example, in some embodiments aplurality of the mixture, such as greater than 30 wt. %, greater than 40wt. %, greater than 50 wt. %, greater than 60 wt. % or greater than 70wt. % based on the total weight of the mixture, comprises an aminepolyether compound or residue thereof or an amide compound or residuethereof represented by one of Formulas I, III, V or X-XXI where q, r andp are independently 0 or 2. For example, in some embodiments, themixture comprises greater than 30 wt %, greater than 40 wt. %, greaterthan 50 wt. %, greater than 60 wt. % or greater than 70 wt. % of anamide compound or residue thereof represented by Formula IV or FormulaVI.

In some embodiments, the invention comprises an amine polyether polymeror an amide polymer, the polymer derived from an amine polyethercompound or an amide compound that is a mixture of amine polyethercompounds or amide compounds, a pharmaceutical composition comprisingsuch an amine polyether polymer or amide polymer, or a method of usingthe same in a therapeutically effective amount to remove a compound or

Other embodiments of the invention include pendant amide polymers orpendant amine polyether polymers formed with amide compounds or residuesthereof or amine polyether compounds or residues thereof as pendantgroups on a polymer or polymerized backbone of a polymer. Such pendantamide polymers and pendant amine polyether polymers may be formed byadding one or more polymerizable groups to one or more amide groups onan amide compound to form an amide monomer or to one or more aminegroups on an amine polyether compound to form an amine polyether monomerand then subsequently polymerizing the polymerizable group to form apendant amide polymer comprising an amide compound or residue thereof ora pendant amine polyether polymer comprising an amine polyether compoundor residue thereof. A schematic example of such an addition follows [itshould be noted in the following that an amide compound or aminepolyether compound designated as “AC” is intended to represent an amidecompound or residue thereof or an amine polyether compound or residuethereof, of the invention, with one of its amine groups depicted forpurposes of illustrating how a polymerizable group may be added to anamide compound or an amine polyether compound]:

Non-limiting examples of other polymerizable groups that may be usedwith amide compounds or residues thereof and with amine polyethercompounds or residues

One or more polymerizable groups may be added to each amide compound oramine polyether compound and thus it is possible to have mixtures ofamide monomers or amine polyether monomers having various pendant ACshaving differing numbers of polymerizable groups. In addition, thependant amide polymers and pendant amine polyether polymers made in thisfashion may be modified, crosslinked, formed into a network orsubstituted post polymerization. Such modification may be performed forany number of reasons, including to improve efficacy, tolerability orreduce side effects.

Amide monomers may also be formed by addition of amide compounds toamine-reactive polymers by reacting one or more amine groups of theamide monomers with one or more amine-reactive groups on theamine-reactive polymers. Amine polyether monomers may also be formed byaddition of amine polyether compounds to amine-reactive polymers byreacting one or more amine groups of the amine polyether monomers withone or more amine-reactive groups on the amine-reactive polymers.Examples of some amine reactive polymers include:

The amide compounds, amide monomers, amine polyether compounds or aminepolyether monomers may also serve as multifunctional monomers to formpolymers. For example, when the amide compounds or the polymers formedfrom the amide monomers or the amine polyether compounds or the polymersformed from the amine polyether monomers are crosslinked, thecrosslinking reaction may be carried out either in solution of bulk(i.e. using the neat amide and neat crosslinking agents) or in dispersedmedia. When a bulk process is used, solvents are selected so that theyco-dissolve the reactants and do not interfere with the crosslinkingreaction. Suitable solvents include water, low boiling alcohols(methanol, ethanol, butanol), dimethylformamide, dimethylsulfoxide,acetone, methylethylketone, and the like.

Other polymerization methods may include a single polymerizationreaction, stepwise addition of individual monomers via a series ofreactions, the stepwise addition of blocks of monomers, combinations ofthe foregoing, or any other method of polymerization, such as, forexample, direct or inverse suspension, condensation, emulsion,precipitation techniques, polymerization in aerosol or using bulkpolymerization/crosslinking methods and size reduction processes such asextrusion and grinding. Processes can be carried out as

Amide compounds, amide monomers, amine polyether compounds and aminepolyether monomers of the invention may be copolymerized with one ormore other monomers or oligomers or other polymerizable groups, may becrosslinked, may have crosslinking or other linking agents or monomerswithin the polymer backbone or as pendant groups or may be formed orpolymerized to form a polymer network or mixed polymer networkcomprising: amide compounds or residues thereof, amide monomers orresidues thereof, amine polyether compounds or residues thereof, aminepolyether monomers or residues thereof, crosslinking agents or residuesthereof, or other linking agents or residues thereof. The network mayinclude multiple connections between the same or different moleculesthat may be direct or may include one or more linking groups such ascrosslinking agents or other linking agents such as monomers oroligomers or residues thereof.

Non-limiting examples of comonomers which may be used alone or incombination include: styrene, substituted styrene, alkyl acrylate,substituted alkyl acrylate, alkyl methacrylate, substituted alkylmethacrylate, acrylonitrile, methacrylonitrile, acrylamide,methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide,N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene,ethylene, vinyl acetate, N-vinyl amide, maleic acid derivatives, vinylether, allyle, methallyl monomers and combinations thereof.Functionalized versions of these monomers may also be used. Additionalspecific monomers or comonomers that may be used in this inventioninclude, but are not limited to, methyl methacrylate, ethylmethacrylate, propyl methacrylate (all isomers), butyl methacrylate (allisomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylicacid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile,α-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (allisomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornylacrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile,styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate,hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (allisomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethylmethacrylate, triethyleneglycol methacrylate, itaconic anhydride,itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropylacrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N—

In some embodiments, amide polymers or amine polyether polymers of theinvention are crosslinked using crosslinking agents, and may notdissolve in solvents, and, at most, swell in solvents. The swellingratio may be measured according to the procedure in the Test Methodssection below and is typically in the range of about 1 to about 20; forexample 2 to 10, 2.5 to 8, 3 to 6 such as less than 5, less than 6, orless than 7. In some embodiments, the amide polymers or amine polyetherpolymers may include crosslinking or other linking agents that mayresult in amide polymers or amine polyether polymers that do not formgels in solvents and may be soluble or partially soluble in somesolvents.

Crosslinking agents are typically compounds having at least twofunctional groups that are selected from a halogen group, carbonylgroup, epoxy group, ester group, acid anhydride group, acid halidegroup, isocyanate group, vinyl group, and chloroformate group. Thecrosslinking agent may be attached to the carbon backbone or to anitrogen of an amide compound or residue thereof, an amide monomer orresidue thereof, an amine polyether compound or residue thereof and/oran amine polyether monomer or residue thereof.

Examples of crosslinking agents that are suitable for synthesis of thepolymers or dendrimers of the present invention include, but are notlimited to, one or more multifunctional crosslinking agents such as:dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates,di(haloalkyl)amides, tri(haloalkyl)amides, diepoxides, triepoxides,tetraepoxides, bis(halomethyl) benzenes, tri(halomethyl) benzenes,tetra(halomethyl) benzenes, epihalohydrins such as epichlorohydrin andepibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyltosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane,bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane,1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dibromopropane,bis(2-chloroethyl)amide, tris(2-chloroethyl)amide, andbis(2-chloroethyl)methylamide, 1,3-butadiene diepoxide, 1,5-hexadienediepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane,1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propyleneglycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2ethanedioldiglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidylglyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidylether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene,resorcinol digylcidyl ether, 1,6-hexanediol diglycidyl ether,trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanoldiglycidyl ether,1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane,1,2-cyclohexanedicarboxylic acid diglycidyl ester,2,2′-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether,1,4-bis(2′,3′-epoxypropyl)perfluoro-n-butane,2,6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3,5,7-tetraone,bisphenol A diglycidyl ether, ethyl5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4h-chromene-2-carboxylate,bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide,1,3-bis(3-glycidoxypropyl)tetramethyldisiloxane,9,9-bis[4-(glycidyloxy)phenyl]fluorine, triepoxyisocyanurate, glyceroltriglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid(S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester,triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerolpropoxylate triglycidyl ether, triphenylolmethane triglycidyl ether,3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-heptacyclopentyltricyclo[7.3.3.15,11]heptasiloxane,4,4′-methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene,bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluenediisocyanate, acrylol chloride, methyl acrylate, ethylene bisacrylamide,pyrometallic dianhydride, succinyl dichloride, dimethylsuccinate. Whenthe crosslinking agent is an alkylhalide compound, a base can be used toscavenge the acid formed during the reaction. Inorganic or organic basesare suitable. NaOH is preferred. The base to crosslinking agent ratio ispreferably between about 0.5 to about 2.

In some embodiments, the crosslinking agents may be introduced into thepolymerization reaction in an amount of from 0.5 to 25 wt. % based onthe total weight of the amide polymer or amine polyether polymer, suchas from about 2 to about 15 wt. %, from about 2 to about 12 wt. %, fromabout 3 to about 10 wt. %, or from about 3 to about 6 wt. %, such as 2,3, 4, 5, 6 wt %. The amount of crosslinking agent necessary may dependon the extent of branching within the amide compound or amine polyethercompound.

In some embodiment the molecular weight of the amide polymers or aminepolyether polymers, may be typically at least about 1000. For example,the molecular weight may be from about 1000 to about 1,000,000, such asabout 1000 to about 750,000, about 1000 to about 500,000, about 1000 toabout 250,000, about 1000 to about 100,000 such as less than 750,000,less than 500,000, 250,000 or less than 100,000.

In some embodiments, the pharmaceutical composition of the presentinvention comprises an amide polymer comprising at least one amidecompound or residue thereof, where the amide compound is represented byFormula III where R₅ independently represents an H radical or an alkylradical, q and r are 0 and p is 2, m independently represents an integerfrom 3-6, such as 3, 4, 5 or 6; and 2-6 wt. % crosslinking agent orresidue thereof, such as 2 wt. %, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. %crosslinking agent, where the crosslinking agent is epichlorohydrin,poly(epichlorohydrin), 1,2-dibromoethane, tris(2-chloroethyl)amide or1,4-butanediol diglycidyl ether. Another pharmaceutical compositionembodiment of the present invention comprises an amide polymercomprising at least one amide compound or residue thereof, where theamide compound is represented by Formula III where R₅ independentlyrepresents an H radical or an alkyl radical, q is 0 and r and p both are2, m independently represents an integer from 3-6, such as 3, 4, 5 or 6,where the compound is crosslinked with a crosslinking agent as definedabove in this paragraph. A further pharmaceutical composition embodimentof the present invention comprises an amide polymer comprising at leastone amide compound or residue thereof, where the amide compound isrepresented by Formula III where R₅ independently represents an Hradical or an alkyl radical, q, r and p are each 2, m independentlyrepresents an integer from 3-6, such as 3, 4, 5 or 6, where the compoundis crosslinked with a crosslinking agent as defined above in thisparagraph.

In some embodiments, the pharmaceutical composition of the presentinvention comprises an amide polymer comprising at least one amidecompound or residue thereof, where the amide compound is represented byFormula V where R₅ independently represents an H radical or an alkylradical, q and r are 0 and p is 2, m independently represents an

Another pharmaceutical composition of the present invention comprises anamide polymer comprising an amide compound or residue thereof, the amidecompound comprising a substituted amide polyol having one or more unitsrepresented by Formula VII where R₅ independently represents an Hradical or an alkyl radical, q and r are 0 and p is 2, m independentlyrepresents an integer from 3-6, such as 3, 4, 5 or 6; and 2-6 wt. %crosslinking agent or residue thereof, such as 2 wt. %, 3 wt. %, 4 wt.%, 5 wt. % or 6 wt. % crosslinking agent, where the crosslinking agentis epichlorohydrin, poly(epichlorohydrin), 1,2-dibromoethane,tris(2-chloroethyl)amide or 1,4-butanediol diglycidyl ether. Anotherpharmaceutical composition embodiment of the present invention comprisesan amide polymer comprising an amide compound or residue thereof, theamide compound comprising a substituted amide polyol having one or moreunits represented by Formula VII where R₅ independently represents an Hradical or an alkyl radical, q is 0 and r and p both are 2, mindependently represents an integer from 3-6, such as 3, 4, 5 or 6, andcrosslinked with a crosslinking agent as defined above in thisparagraph. A further pharmaceutical composition embodiment of thepresent invention comprises an amide polymer comprising an amidecompound or residue thereof, the amide compound comprising a substitutedamide polyol having one or more units represented by Formula VII whereR₅ independently represents an H radical or an alkyl radical, q, r and pare each 2, m independently represents an integer

In some embodiments, the pharmaceutical composition of the presentinvention comprises an amine polyether polymer comprising at least oneamine polyether compound or residue thereof, where the amine polyethercompound is represented by Formula X where R₅ independently representsan H radical or an alkyl radical, q and r are 0 and p is 2, mindependently represents an integer from 3-6, such as 3, 4, 5 or 6; and2-6 wt. % crosslinking agent or residue thereof, such as 2 wt. %, 3 wt.%, 4 wt. %, 5 wt. % or 6 wt. % crosslinking agent, where thecrosslinking agent is epichlorohydrin, poly(epichlorohydrin),1,2-dibromoethane, tris(2-chloroethyl)amide or 1,4-butanediol diglycidylether. Another pharmaceutical composition embodiment of the presentinvention comprises an amine polyether polymer comprising at least oneamine polyether compound or residue thereof, where the amine polyethercompound is represented by Formula X where R₅ independently representsan H radical or an alkyl radical, q is 0 and r and p both are 2, mindependently represents an integer from 3-6, such as 3, 4, 5 or 6,where the compound is crosslinked with a crosslinking agent as definedabove in this paragraph. A further pharmaceutical composition embodimentof the present invention comprises an amine polyether polymer comprisingat least one amine polyether compound or residue thereof, where theamine polyether compound is represented by Formula X where R₅independently represents an H radical or an alkyl radical, q, r and pare each 2, m independently represents an integer from 3-6, such as 3,4, 5 or 6, where the compound is crosslinked with a crosslinking agentas defined above in this paragraph.

In some embodiments, the invention is a compound or composition ormethod for removing an anion, such as organophosphate or phosphate, fromthe gastrointestinal tract of an animal by administering atherapeutically effective amount of an amide polymer that comprises anamide dendrimer having a core that is a residue of an amide polyol and aresidue of one or more substituted or un-substituted α, β unsaturatednitriles, where the amide polyol comprises a residue of an organicpolyacid or ester thereof and a residue of an amine polyol.

Another pharmaceutical composition of the present invention comprises anamide polymer that comprises an amide dendrimer or residue thereofhaving a core that is a residue of an amide polyol and a residue of oneor more acrylonitriles, where the amide polyol is a residue of tartaricacid or other aldaric acid or an ester of tartaric acid or other aldaricacid, and a residue of tris(hydroxymethyl)aminomethane; where thedendrimer is crosslinked with

Another pharmaceutical composition of the present invention comprises apolymer network having a plurality of units represented by Formula VIIIwhere n is from 3-6, the composition also having a plurality of unitsrepresented by Formula IX.

The polymers of some embodiments may be formed using a polymerizationinitiator. Generally, any initiator may be used including cationic andradical initiators. Some examples of suitable initiators that may beused include: the free radical peroxy and azo type compounds, such asazodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate,2,2′-azobis(isobutyronitrile),2,2′-azobis(N,N′-dimethyleneisobutyramidine)dihydrochloride,2,2′-azobis(2-amidinopropane)dihydrochloride,2,2′-azobis(N,N′-dimethyleneisobutyramidine),1,1′-azobis(1-cyclohexanecarbonitrile), 4,4′-azobis(4-cyanopentanoicacid), 2,2′-azobis(isobutyramide) dihydrate,2,2′-azobis(2-methylpropane), 2,2′-azobis(2-methylbutyronitrile), VAZO67, cyanopentanoic acid, the peroxy pivalates, dodecylbenzene peroxide,benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetylperoxide, dicumyl peroxide, cumyl hydroperoxide, dimethylbis(butylperoxy)hexane.

In some embodiments, any of the nitrogen atoms within the amidecompounds or residues thereof or amine polyether compounds or residuesthereof according to embodiments of the invention may optionally bequaternized to yield the corresponding positively charged tertiarynitrogen group, such as for example, an ammonium or substituted ammoniumgroup. Any one or more of the nitrogen atoms in the amide compound orresidue thereof or amine polyether compound or residue thereof may bequaternized and such quaternization, when present, is not limited to orrequired to include terminal amine nitrogen atoms. In some embodiments,this quaternization may result in additional network formation and maybe the result of addition of crosslinking, linking or addition of aminereactive groups to the nitrogen. The ammonium groups may be associatedwith a pharmaceutically acceptable counterion.

In some embodiments, amide compounds, amide polymers, amine polyethercompounds and amine polyether polymers of the invention may be partiallyor fully quaternized or partially or fully protonated, with apharmaceutically acceptable counterion, which may be organic ions,inorganic ions, or a combination thereof. Examples of some suitableinorganic ions include halides (e.g., chloride, bromide or iodide)carbonates, bicarbonates, sulfates, bisulfates, hydroxides, nitrates,persulfates and sulfites. Examples of some suitable organic ions includeacetates, ascorbates, benzoates, citrates, dihydrogen citrates, hydrogencitrates, oxalates, succinates, tartrates, taurocholates, glycocholates,and cholates. Preferred ions include chlorides and carbonates.

In some embodiments, amide compounds, amide polymers, amine polyethercompounds and amine polyether polymers of the invention may beprotonated such that the fraction of protonated nitrogen atoms is from 1to 25%, preferably 3 to 25%, more preferably 5 to 15%.

In one embodiment, a pharmaceutically acceptable amide polymer or aminepolyether polymer is an amide polymer or amine polyether polymer inpartially or fully protonated form and comprises a carbonate anion. Inone embodiment the pharmaceutically acceptable amide polymer orpharmaceutically acceptable amine polyether polymer is in partially orfully protonated form and comprises a mixture of carbonate andbicarbonate anions.

In some embodiments, compounds and polymers of the invention arecharacterized by their ability to bind compounds or ions. Preferably thecompounds or polymers of the invention bind anions, more preferably theybind organophosphates, phosphate and/or oxalate, and most preferablythey bind organophosphates or phosphate. For illustration, anion-bindingamide polymers, anion binding amine polyether polymers and especiallyorganophosphate or phosphate-binding amide polymers and organophosphateor phosphate-binding amine polyether polymers will be described;however, it is understood that this description applies equally, withappropriate modifications that will be apparent to those of skill in theart, to other ions, compounds and solutes. Amide polymers and aminepolyether polymers may bind an ion, e.g., an anion when they associatewith the ion, generally though not necessarily in a noncovalent manner,with sufficient association strength that at least a portion of the ionremains bound under the in vitro or in vivo conditions in which thepolymer is used for sufficient time to effect a removal of the ion fromsolution or from the body. A target ion may be an ion to which the amidepolymer or amine polyether polymer binds, and usually refers to the ionwhose binding to the amide polymer or amine

For example, some of the amide polymers and amine polyether polymersdescribed herein exhibit organophosphate or phosphate bindingproperties. Phosphate binding capacity is a measure of the amount ofphosphate ion a phosphate binder can bind in a given solution. Forexample, binding capacities of phosphate binders can be measured invitro, e.g., in water or in saline solution, or in vivo, e.g., fromphosphate urinary excretion, or ex vivo, for example using aspirateliquids, e.g., chyme obtained from lab animals, patients or volunteers.Measurements can be made in a solution containing only phosphate ion, orat least no other competing solutes that compete with phosphate ions forbinding to the amide polymer or amine polyether polymer. In these cases,a non interfering buffer may be used. Alternatively, measurements can bemade in the presence of other competing solutes, e.g., other ions ormetabolites, that compete with phosphate ions (the target solute) forbinding to the amide polymer or amine polyether polymer.

Ion binding capacity for an amide polymer or amine polyether polymer maybe measured as indicated in the Test Methods. Some embodiments have aphosphate binding capacity which can be greater than about 0.2, 0.5,1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12, 14, 16, 18or greater than about 20 mmol/g. In some embodiments, the in vitrophosphate binding capacity of amide polymers or amine polyether polymersof the invention for a target ion is greater than about 0.5 mmol/g,preferably greater than about 2.5 mmol/g, even more preferably greaterthan about 3 mmol/g, even more preferably greater than about 4 mmol/g,and yet even more preferably greater than about 6 mmol/g. In someembodiments, the phosphate binding capacity can range from about 0.2mmol/g to about 20 mmol/g, such as about 0.5 mmol/g to about 10 mmol/g,preferably from about 2.5 mmol/g to about 8 mmol/g, and even morepreferably from about 3 mmol/g to about 6 mmol/g. Phosphate binding maybe measured according to the techniques described in the Test Methodssection below.

In some embodiments, amide compounds, amide polymers, amine polyethercompounds, amine polyether polymers and compositions of the inventionmay reduce urinary phosphorous of a patient in need thereof by 5-100%,such as 10-75%, 25-65%, or 45-60%. Some embodiments may reduce urinaryphosphorous by greater than 10%, greater than 20%, greater than 30%,greater than 40%, greater than 45%, greater than 50% or greater than60%. Reduction of urinary phosphorous may be measured according to themethods detailed in the Test Methods section below.

In some embodiments, amide polymers, amine polyether polymers andcompositions of the invention may reduce blood phosphate of a patient inneed thereof by 5-100%, such as 10-75%, 25-65%, or 45-60%. Someembodiments may reduce blood phosphate levels by greater than 10%,greater than 20%, greater than 30%, greater than 40%, greater than 45%,greater than 50% or greater than 60%.

When crosslinked, some embodiments of the amide compounds and aminepolyether compounds of the invention form a gel in a solvent, such as ina simulated gastrointestinal medium or a physiologically acceptablemedium.

One aspect of the invention is core-shell compositions comprising apolymeric core and shell. In some embodiments, the polymeric corecomprises the amide polymers or amine polyether polymers describedherein. The shell material can be chemically anchored to the corematerial or physically coated. In the former case, the shell can begrown on the core component through chemical means, for example by:chemical grafting of shell polymer to the core using livingpolymerization from active sites anchored onto the core polymer;interfacial reaction, i.e., a chemical reaction located at the coreparticle surface, such as interfacial polycondensation; and using blockcopolymers as suspending agents during the core particle synthesis.

In some embodiments, the interfacial reaction and use of block polymersare the techniques used when chemical methods are used. In theinterfacial reaction pathway, typically, the periphery of the coreparticle is chemically modified by reacting small molecules ormacromolecules on the core interface. For example, an amide containingion-binding core particle or an amine polyether containing ion-bindingcore particle is reacted with a polymer containing amine reactive groupssuch as epoxy, isocyanate, activated esters, halide groups to form acrosslinked shell around the core.

In another embodiment, the shell is first prepared using interfacialpolycondensation or solvent coacervation to produce capsules. Theinterior of the capsule is then filled up with core-forming precursorsto build the core within the shell capsule.

In some embodiments, using the block copolymer approach, an amphiphilicblock copolymer can be used as a suspending agent to form the coreparticle in an inverse or direct suspension particle forming process.When an inverse water-in-oil suspension process is used, then the blockcopolymer comprises a first block soluble in the continuous oil phaseand another hydrophilic block contains functional groups that can reactwith the core polymer. When added to the aqueous phase, along withcore-forming precursor, and the oil phase, the block copolymer locatesto the water-in-oil interface and acts as a suspending

When the shell material is physically adsorbed on the core material,well known techniques of microencapsulation such as solventcoacervation, fluidized bed spray coater, or multiemulsion processes canbe used. One method of microencapsulation is the fluidized bed spraycoater in the Wurster configuration. In yet another embodiment, theshell material is only acting temporarily by delaying the swelling ofthe core particle while in the mouth and esophagus, and optionallydisintegrates in the stomach or duodenum. The shell is then selected inorder to hinder the transport of water into the core particle, bycreating a layer of high hydrophobicity and very low liquid waterpermeability.

In one embodiment the shell material carries negative charges whilebeing in the milieu of use. Not being limited to one mechanism ofaction, it is thought that negatively charged shell material coated onanion-binding beads enhance the binding of small inorganic ions with alow charge density (such as phosphate) over competing ions with greatervalency or size. Competing anions such as citrate, bile acids and fattyacids among others, may thus have a lesser relative affinity to theanion binding core possibly as a result of their limited permeabilityacross the shell.

In some embodiments, shell materials are polymers carrying negativecharges in the pH range typically found in the intestine. Examplesinclude, but are not limited to, polymers that have pendant acid groupssuch as carboxylic, sulfonic, hydrosulfonic, sulfamic, phosphoric,hydrophosphoric, phosphonic, hydrophosphonic, phosphoramidic, phenolic,boronic and a combination thereof. The polymer can be protonated orunprotonated; in the latter case the acidic anion can be neutralizedwith pharmaceutically acceptable cations such as Na, K, Li, Ca, Mg, andNH₄.

In another embodiment the polyanion can be administered as a precursorthat ultimately activates as a polyanion: for instance certain labileester or anhydride forms of either polysulfonic or polycarboxylic acidsare prone to hydrolysis in the acidic environment of the stomach and canconvert to the active anions.

The shell polymers can be either linear, branched, hyperbranched,segmented (i.e. backbone polymer arranged in sequence of contiguousblocks of which at least one contains pendant acidic groups),comb-shaped, star-shaped or crosslinked in a network, fully and

Additional shell polymers include: poly(styrene sulfonate),Polycarbophil®; Polyacrylic acid(s); carboxymethyl cellulose, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate as sold underthe tradename HP-50 and HP-55 (Shin-Etsu Chemical Co., Ltd.), celluloseacetate trimellitate, cellulose acetate, cellulose acetate butyrate,cellulose acetate propionate, ethyl cellulose, cellulose derivatives,such as hydroxypropylmethylcellulose, methylcelluose,hydroxylethylcellulose, hydroxyethylmethylcellulose,hydroxylethylethylcelluose and hydroxypropylethylcellulose and cellulosederivatives such as cellulose ethers useful in film coatingformulations, polyvinyl acetate phthalate, carrageenan, alginate, orpoly(methacrylic acid) esters, acrylic/maleic acid copolymers,styrene/maleic acid polymers, itaconic acid/acrylic copolymers, andfumaric/acrylic acid copolymers, polyvinyl acetal diethylaminoacetate,as sold under the tradename AEA (Sankyo Co., Ltd.),methylvinylether/maleic acid copolymers and shellac.

In some embodiments the shell polymers are selected amongstpharmaceutically acceptable polymers such as Eudragit L100-55 andEudragit L100 (a methylmethacrylate-methacrylic acid (1:1) copolymer,Degussa/Rohm), Carbopol 934 (polyacrylic acid, Noveon), C-A-P NF(cellulose acetate phthalate—Eastman), Eastacryl (methacrylic acidesters—Eastman), Carrageenan and Alginate (FMC Biopolymer), Anycoat—P(Samsung Fine Chemicals—HPMC Phthalate), or Aqualon (carboxymethylcellulose—

The shell can be coated by a variety of methods. In one embodiment, theshell materials are added in the drug formulation step as an activeexcipient; for example, the shell material can be included in a solidformulation as a powder, which is physically blended with theorganophosphate or phosphate-binding polymer and other excipients,optionally granulated, and compressed to form a tablet. Thus, in someembodiments, the shell material need not cover the core material in thedrug product. For example, the acidic shell polymer may be addedtogether with the anion binding core polymer formulated in the shape ofa tablet, capsule, gel, liquid, etc, wafer, extrudates and the shellpolymer can then dissolve and distribute itself uniformly as a shellcoating around the core while the drug product equilibrates in themouth, esophagus or ultimately in the site of action, i.e. the GI tract.

In some embodiments, the shell is a thin layer of shell polymer. Thelayer can be a molecular layer of polyanion on the core particlesurface. The weight to core ratio can be between about 0.0001% to about30%, preferably comprised between about 0.01% to about 5%, such asbetween about 0.1% to about 5%.

The shell polymers have a minimum molecular weight such that they do notfreely permeate within the core pore volume nor elute from the coresurface. In some embodiments, the molecular weight (Mw) of the shellacidic polymer is above about 1000 g/mole, such as above about 5000g/mole, and or even above about 20,000 g/mole

The anionic charge density of the shell material (as prevailing in themilieu of use) is may be between 0.5 mEq/gr to 22 mEq/gr, such as 2mEq/gr to 15 mEq/gr. If a coating process is used to form the shell onthe polymer particles as part of the manufacture of the dosage form,then procedures known from those skilled-in-the-art in thepharmaceutical industry are applicable. In one embodiment, the shell isformed in a fluidized bed coater (Wurster coater). In an alternateembodiment, the shell is formed through controlled precipitation orcoascervation, wherein the polymer particles are suspended in a polymersolution, and the solvent properties are changed in such a way as toinduce the polymer to precipitate onto or coat the polymer particles.

Suitable coating processes include the procedures typically used in thepharmaceutical industry. Typically, selection of the coating method isdictated by a number of parameters, that include, but are not limited tothe form of the shell material (bulk, solution, emulsion, suspension,melt) as well as the shape and nature of the core material (sphericalbeads, irregular shaped, etc.), and the amount of shell deposited. Inaddition, the

The term “phosphate imbalance disorder” as used herein refers toconditions in which the level of phosphorus present in the body isabnormal. One example of a phosphate imbalance disorder includeshyperphosphatemia. The term “hyperphosphatemia” as used herein refers toa condition in which the element phosphorus is present in the body at anelevated level. Typically, a patient is often diagnosed withhyperphosphatemia if the blood phosphate level is, for example, aboveabout 4.0 or 4.5 milligrams per deciliter of blood, for example aboveabout 5.0 mg/dl, such as above about 5.5 mg/dl, for example above 6.0mg/dl, and/or the patient has a severely impaired glomerular filtrationrate such as, for example, less than about 20% of normal. The presentinvention may also be used to treat patients suffering fromhyperphosphatemia in End Stage Renal Disease and who are also receivingdialysis treatment (e.g., hemodialysis or peritoneal dialysis).

Other diseases that can be treated with the methods, compounds,polymers, compositions, and kits of the present invention includehypocalcemia, hyperparathyroidism, depressed renal synthesis ofcalcitriol, tetany due to hypocalcemia, renal insufficiency, and ectopiccalcification in soft tissues including calcifications in joints, lungs,kidney, conjuctiva, and myocardial tissues. Also, the present inventioncan be used to treat Chronic Kidney Disease (CKD), End Stage RenalDisease (ESRD) and dialysis patients, including prophylactic treatmentof any of the above.

The amide polymers, amine polyether polymers and compositions describedherein can be used as an adjunct to other therapies e.g. those employingdietary control of phosphorus intake, dialysis, inorganic metal saltsand/or other polymer resins.

The compositions of the present invention are also useful in removingchloride, bicarbonate, oxalate, and bile acids from the gastrointestinaltract. Amide polymers and amine polyether polymers removing oxalatecompounds or ions find use in the treatment of oxalate imbalancedisorders, such as oxalosis or hyperoxaluria that increases the risk ofkidney stone formation. Amide polymers and amine polyether polymersremoving chloride compounds or ions find use in treating acidosis,heartburn, acid reflux disease, sour stomach or gastritis, for example.In some embodiments, the amide polymers, amine polyether polymers andcompositions of the present invention are useful for removing fattyacids, bilirubin, and related compounds. Some embodiments may also bindand remove high molecular weight molecules like proteins, nucleic acids,vitamins or cell debris.

The present invention provides methods, pharmaceutical compositions,polymers, compounds and kits for the treatment of animals. The term“animal” or “animal subject” or “patient” as used herein includes humansas well as other mammals (e.g., in veterinary treatments, such as in thetreatment of dogs or cats, or livestock animals such as pigs, goats,cows, horses, chickens and the like). One embodiment of the invention isa method of removing phosphorous-containing compounds such asorganophosphates or phosphate from the gastrointestinal tract, such asthe stomach, small intestine or large intestine of an animal byadministering a therapeutically effective amount of at least one of theamide polymers or amine polyether polymers described herein.

The term “treating” and its grammatical equivalents as used hereinincludes achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication, amelioration, or preventionof the underlying disorder being treated. For example, in ahyperphosphatemia patient, therapeutic benefit includes eradication oramelioration of the underlying hyperphosphatemia. Also, a therapeuticbenefit is achieved with the eradication, amelioration, or prevention ofone or more of the physiological symptoms associated with the underlyingdisorder such that an improvement is observed in the patient,notwithstanding that the patient may still be afflicted with theunderlying disorder. For example, administration of amide polymers oramine polyether polymers, described herein, to a patient suffering fromrenal insufficiency and/or hyperphosphatemia provides therapeuticbenefit not only when the patient's serum phosphate level is decreased,but also when an improvement is observed in the patient with respect toother disorders that accompany renal failure and/or hyperphosphatemialike ectopic calcification and renal osteodistrophy. For prophylacticbenefit, for example, the amide polymers or amine polyether polymers maybe administered to a patient at risk of developing hyperphosphatemia orto a patient reporting one or more of the physiological symptoms ofhyperphosphatemia, even though a diagnosis of hyperphosphatemia may nothave been made.

The compositions may also be used to control serum phosphate in subjectswith elevated phosphate levels, for example, by changing the serum levelof phosphate towards a normal or near normal level, for example, towardsa level that is within 10% of the normal level of a healthy patient.

Other embodiments of the invention are directed towards pharmaceuticalcompositions comprising at least one of the amide polymers or apharmaceutically acceptable salt of the amide polymer, or at least oneof the amine polyether polymers or a pharmaceutically acceptable salt ofthe amine polyether polymer and one or more

The excipients or carriers are “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. The formulations can convenientlybe presented in unit dosage form and can be prepared by any suitablemethod. The methods typically include the step of bringing intoassociation the agent with the excipients or carriers such as byuniformly and intimately bringing into association the amide polymer oramine polyether polymer with the excipients or carriers and then, ifnecessary, dividing the product into unit dosages thereof.

The pharmaceutical compositions of the present invention includecompositions wherein the amide compounds, amide polymers, aminepolyether compounds and/or amine polyether polymers are present in atherapeutically effective amount, i.e., in an amount effective toachieve therapeutic and/or prophylactic benefit. The actual amounteffective for a particular application will depend on the patient (e.g.age, weight) the condition being treated; and the route ofadministration.

The dosages of the amide polymers or amine polyether polymers in animalswill depend on the disease being, treated, the route of administration,and the physical characteristics of the animal being treated. Suchdosage levels in some embodiments for either therapeutic and/orprophylactic uses may be from about 1 gm/day to about 30 gm/day, forexample from about 2 gm/day to about 20 gm/day or from about 3 gm/day toabout 7 gm/day. The dose of the amide polymers or amine polyetherpolymers described herein can be less than about 50 gm/day, less thanabout 40 gm/day, less than about 30 gm/day, less than about 20 gm/day,and less than about 10 gm/day.

Typically, the amide polymers or amine polyether polymers can beadministered before or after a meal, or with a meal. As used herein,“before” or “after” a meal is typically within two hours, preferablywithin one hour, more preferably within thirty minutes, most preferablywithin ten minutes of commencing or finishing a meal, respectively.

Generally, it is preferred that the amide polymers or amine polyetherpolymers are administered along with meals. The amide polymers or aminepolyether polymers may be administered one time a day, two times a day,or three times a day. Preferably the amide polymers or amine polyetherpolymers are administered once a day with the largest meal.

Preferably, the amide polymers or amine poly ether polymers may be usedfor therapeutic and/or prophylactic benefits and can be administeredalone or in the form of a pharmaceutical composition. The pharmaceuticalcompositions comprise the amide polymers or amine polyether polymers,one or more pharmaceutically acceptable carriers, diluents orexcipients, and optionally additional therapeutic agents. For example,the amide polymers or amine polyether polymers of the present inventionmay be co-administered with other active pharmaceutical agents dependingon the condition being treated. Examples of pharmaceutical agents thatmay be co-administered include, but are not limited to:

Other phosphate sequestrants including pharmaceutically acceptablelanthanum, calcium, aluminum, magnesium and zinc compounds, such asacetates, carbonates, oxides, hydroxides, citrates, alginates, andketoacids thereof.

Calcium compounds, including calcium carbonate, acetate (such as PhosLo®calcium acetate tablets), citrate, alginate, and ketoacids, have beenutilized for phosphate binding.

Aluminium-based phosphate sequestrants, such as Amphojel® aluminiumhydroxide gel, have also been used for treating hyperphosphatemia. Thesecompounds complex with intestinal phosphate to form highly insolublealuminium phosphate; the bound phosphate is unavailable for absorptionby the patient.

The most commonly used lanthanide compound, lanthanum carbonate(Fosrenol®) behaves similarly to calcium carbonate.

Other phosphate sequestrants suitable for use in the present inventioninclude pharmaceutically acceptable magnesium compounds. Variousexamples of pharmaceutically acceptable magnesium compounds aredescribed in U.S. Provisional Application No. 60/734,593 filed Nov. 8,2005, the entire teachings of which are incorporated herein byreference. Specific suitable examples include magnesium oxide, magnesiumhydroxide, magnesium halides (e.g., magnesium fluoride, magnesiumchloride, magnesium bromide and magnesium iodide), magnesium alkoxides(e.g., magnesium ethoxide and magnesium isopropoxide), magnesiumcarbonate, magnesium bicarbonate, magnesium formate, magnesium acetate,magnesium trisilicates, magnesium salts of organic acids, such asfumaric acid, maleic acid, acrylic acid, methacrylic acid, itaconic acidand styrenesulfonic acid, and a combination thereof.

Various examples of pharmaceutically acceptable zinc compounds aredescribed in PCT Application No. PCT/US2005/047582 filed Dec. 29, 2005,the entire teachings of which are incorporated herein by reference.Specific suitable examples of

When referring to any of the above-mentioned phosphate sequestrants, itis to be understood that mixtures, polymorphs and solvates thereof areencompassed.

In some embodiments, a mixture of the phosphate sequestrants describedabove can be used in the invention in combination with pharmaceuticallyacceptable ferrous iron salts.

In other embodiments, the phosphate sequestrant used in combination withcompounds of the present invention is not a pharmaceutically acceptablemagnesium compound. In yet other embodiments, the phosphate sequestrantused in combination with the pharmaceutically acceptable amidecompounds, amide polymers, amine polyether compounds and/or aminepolyether polymers is not a pharmaceutically acceptable zinc compound.

The invention also includes methods and pharmaceutical compositionsdirected to a combination therapy of the amide polymers or aminepolyether polymers in combination with a phosphate transport inhibitoror an alkaline phosphatase inhibitor. Alternatively, a mixture of theamide polymers or amine polyether polymers is employed together with aphosphate transport inhibitor or an alkaline phosphatase inhibitor.

Suitable examples of phosphate transport inhibitors can be found inco-pending U.S. Application Publication Nos. 2004/0019113 and2004/0019020 and WO 2004/085448, the entire teachings of each of whichare incorporated herein by reference.

A large variety of organic and inorganic molecules are inhibitors toalkaline phosphatase (ALP) (see, for example, U.S. Pat. No. 5,948,630,the entire teachings of which are incorporated herein by reference).Examples of alkaline phosphatase inhibitors include orthophosphate,arsenate, L-phenylalanine, L-homoarginine, tetramisole, levamisole,L-p-Bromotetramisole, 5,6-Dihydro-6-(2-naphthyl)imidazo-[2,1-b]thiazole(napthyl) and derivatives thereof. The preferred inhibitors include, butare not limited to, levamisole, bromotetramisole, and5,6-Dihydro-6-(2-naphthyl)imidazo-[2,1-b]thiazole and derivativesthereof.

This co-administration can include simultaneous administration of thetwo agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. For example, for thetreatment of hyperphosphatemia, the amide polymers or amine polyetherpolymers may be co-administered with calcium salts which are used totreat hypocalcemia resulting from hyperphosphatemia.

The pharmaceutical compositions of the invention can be formulated as atablet, sachet, slurry, food formulation, troche, capsule, elixir,suspension, syrup, wafer, chewing gum or lozenge.

Preferably, the amide polymers, amine polyether polymers or thepharmaceutical compositions comprising the amide polymers or aminepolyether polymers is administered orally. Illustrative of suitablemethods, vehicles, excipients and carriers are those described, forexample, in Remington's Pharmaceutical Sciences, 19th ed., the contentsof which is incorporated herein by reference.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Suitable techniquesfor preparing pharmaceutical compositions of the amide polymers andamine polyether polymers are well known in the art.

In some aspects of the invention, the amide polymer(s) or aminepolyether polymer(s) provide mechanical and thermal properties that areusually performed by excipients, thus decreasing the amount of suchexcipients required for the formulation. In some embodiments the amidepolymer or amine polyether polymer constitutes over about 30 wt. %, forexample over about 40 wt. %, over about 50 wt. %, preferably over about60 wt. %, over about 70 wt. %, more preferably over about 80 wt. %, overabout 85 wt. % or over about 90 wt. % of the composition, the remaindercomprising suitable excipient(s).

In some embodiments, the compressibility of the tablets is stronglydependent upon the degree of hydration (moisture content) of the amidepolymer or amine polyether polymer. Preferably, the amide polymer oramine polyether polymer has a moisture content of about 5% by weight orgreater, more preferably, the moisture content is from about 5% to about9% by weight, and most preferably about 7% by weight. It is to beunderstood that in embodiments in which the amide polymer or aminepolyether polymer is hydrated, the water

The tablet can further comprise one or more excipients, such ashardeners, glidants and lubricants, which are well known in the art.Suitable excipients include colloidal silicon dioxide, stearic acid,magnesium silicate, calcium silicate, sucrose, calcium stearate,glyceryl behenate, magnesium stearate, talc, zinc stearate and sodiumstearylfumarate.

The tablet core of embodiments of the invention may be prepared by amethod comprising the steps of: (1) hydrating or drying the amidepolymer or amine polyether polymer to the desired moisture level; (2)blending the amide polymer or amine polyether polymer with anyexcipients; and (3) compressing the blend using conventional tabletingtechnology.

In some embodiments, the invention relates to a stable, swallowablecoated tablet, particularly a tablet comprising a hydrophilic core, suchas a tablet comprising the amide polymer or amine polyether polymer, asdescribed above. In one embodiment, the coating composition comprises acellulose derivative and a plasticizing agent. The cellulose derivativeis, preferably, hydroxypropylmethylcellulose (HPMC). The cellulosederivative can be present as an aqueous solution. Suitablehydroxypropylmethylcellulose solutions include those containing HPMC lowviscosity and/or HPMC high viscosity. Additional suitable cellulosederivatives include cellulose ethers useful in film coatingformulations. The plasticizing agent can be, for example, an acetylatedmonoglyceride such as diacetylated monoglyceride. The coatingcomposition can further include a pigment selected to provide a tabletcoating of the desired color. For example, to produce a white coating, awhite pigment can be selected, such as titanium dioxide.

In one embodiment, the coated tablet of the invention can be prepared bya method comprising the step of contacting a tablet core of theinvention, as described above, with a coating solution comprising asolvent, at least one coating agent dissolved or suspended in thesolvent and, optionally, one or more plasticizing agents. Preferably,the solvent is an aqueous solvent, such as water or an aqueous buffer,or a mixed aqueous/organic solvent. Preferred coating agents includecellulose derivatives, such as hydroxypropylmethylcellulose. Typically,the tablet core is contacted with the coating solution until the weightof the tablet core has increased by an amount ranging from about 4% toabout 6%, indicating the deposition of a suitable coating on the tabletcore to form a coated tablet.

Other pharmaceutical excipients useful in the some compositions of theinvention include a binder, such as microcrystalline cellulose,carbopol, providone and xanthan gum; a flavoring agent, such asmannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant,such as vegetable based fatty acids; and, optionally, a disintegrant,such as croscarmellose sodium, gellan gum, low-substituted hydroxypropylether of cellulose, sodium starch glycolate. Such additives and othersuitable ingredients are well-known in the art; see, e.g., Gennaro A R(ed), Remington's Pharmaceutical Sciences, 19th Edition.

In some embodiments the amide polymers or amine polyether polymers ofthe invention are provided as pharmaceutical compositions in the form ofchewable tablets. In addition to the active ingredient, the followingtypes of excipients are commonly used: a sweetening agent to provide thenecessary palatability, plus a binder where the former is inadequate inproviding sufficient tablet hardness; a lubricant to minimize frictionaleffects at the die wall and facilitate tablet ejection; and, in someformulations a small amount of a disintegrant is added to facilitatemastication. In general excipient levels in currently-available chewabletablets are on the order of 3-5 fold of active ingredient(s) whereassweetening agents make up the bulk of the inactive ingredients. In someembodiments the invention provides a pharmaceutical compositionformulated as a chewable tablet, comprising an amide polymer or aminepolyether polymer described herein, a filler, and a lubricant. In someembodiments the invention provides a pharmaceutical compositionformulated as a chewable tablet, comprising an amide polymer or aminepolyether polymer described herein, a filler, and a lubricant, whereinthe filler is chosen from the group consisting of sucrose, mannitol,xylitol, maltodextrin, fructose, and sorbitol, and wherein the lubricantis a magnesium fatty acid salt, such as magnesium stearate.

In one embodiment, the amide polymer or amine polyether polymer ispre-formulated with a high Tg/high melting point low molecular weightexcipient such as mannitol, sorbose, sucrose in order to form a solidsolution wherein the polymer and the excipient are intimately mixed.Methods of mixing such as extrusion, spray-drying, chill drying,lyophilization, or wet granulation are useful. Indication of the levelof mixing is given by known physical methods such as differentialscanning calorimetry or dynamic mechanical analysis.

In some embodiments the amide polymers or amine polyether polymers ofthe invention are provided as pharmaceutical compositions in the form ofliquid formulations. In some embodiments the pharmaceutical compositioncontains polymer dispersed in a suitable

In some embodiments, the pharmaceutical compositions may be in the formof a powder formulation packaged as a sachet that may be mixed withwater or other ingestible liquid and administered orally as a drink(solution or suspension). In order to ensure that such formulationsprovide acceptable properties to the patient such as mouth feel andtaste, a pharmaceutically acceptable anionic stabilizer may be includedin the formulation.

Examples of suitable anionic stabilizers include anionic polymers suchas: an anionic polypeptide, an anionic polysaccharide, or a polymer ofone or more anionic monomers such as polymers of mannuronic acid,guluronic acid, acrylic acid, methacrylic acid, glucuronic acid glutamicacid or a combination thereof, and pharmaceutically acceptable saltsthereof. Other examples of anionic polymers include cellulose, such ascarboxyalkyl cellulose or a pharmaceutically acceptable salt thereof.The anionic polymer may be a homopolymer or copolymer of two or more ofthe anionic monomers described above. Alternatively, the anioniccopolymer may include one or more anionic monomers and one or moreneutral comonomers such as olefinic anionic monomers such as vinylalcohol, acrylamide, and vinyl formamide.

Examples of anionic polymers include alginates (e.g. sodium alginate,potassium alginate, calcium alginate, magnesium alginate, ammoniumalginate, and esters of alginate), carboxymethyl cellulose, polylacticacid, polyglutamic acid, pectin, xanthan, carrageenan, furcellaran, gumArabic, karaya gum, gum ghatti, gum carob, and gum tragacanth. Preferredanionic polymers are alginates and are preferably esterified alginatessuch as a C2-C5-diol ester of alginate or a C3-C5 triol ester ofalginate. As used herein an “esterified alginate” means an alginic acidin which one or more of the carboxyl groups have of the alginic acid areesterified. The remainder of the carboxylic acid groups in the alginateare optionally neutralized (partially or completely) as pharmaceuticallyacceptable salts. For example, propylene glycol alginate is an ester ofalginic acid in which some of the carboxyl groups are esterified withpropylene glycol, and the remainder of the carboxylic acid groups areoptionally neutralized with pharmaceutically acceptable salts. Morepreferably, the anionic polymer is ethylene glycol alginate, propyleneglycol alginate or glycerol alginate, with propylene glycol alginateeven more preferred.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

It will be apparent to one of ordinary skill in the art that manychanges and modification can be made to the disclosures presented hereinwithout departing from the spirit or scope of the appended claims.

EXAMPLES Example 1 Synthesis of an Amide Polyol

To a three-necked flask equipped with a magnetic stir bar was added 9 gof dimethyl L-tartarate, 12.85 g of tris(hydroxymethyl)aminomethane and28 ml of methanol and the resulting solution was stirred at 50° C. for20 hours. The addition of heat was stopped, and the solution wasself-cooled to 42° C. and then filtered and dried at 30° C. in a vacuumoven for 20 hours to give 11.3 g of a white solid.

Test Methods Amide Polymer/Amine Polyether Polymer Urinary PhosphorousReduction (In Vivo-Rats)

House male Sprague Dawley (SD) rats are used for the experiments. Therats are placed singly in wire-bottom cages, fed with Purina 5002 diet,and allowed to acclimate for at least 5 days prior to experimental use.

To establish baseline phosphorus excretion, the rats are placed inmetabolic cages for 48 hours. Their urine is collected and itsphosphorus content analyzed with a Hitachi analyzer to determinephosphorus excretion in mg/day. Any rats with outlying values areexcluded; and the remainder of the rats are distributed into groups.

Purina 5002 is used as the standard diet. The amide polymer or aminepolyether polymer being tested is mixed with Purina 5002 to result in afinal concentration 0.25%, 0.35%, 0.5% and 1% by weight of the feed.Cellulose at 0.5% by weight is used as a negative control. Sevelamer isused as a positive control. In the event that a high-fat diet is used,rats are given feed comprising Purina 5002, 0.25%, 0.35%, 0.5% and 1% byweight of the feed of the polymer and 10% by weight of the feed ofpurified Olive oil, with the purified olive oil commercially availablefrom Sigma. For each rat, 200 g of diet is prepared.

Each rat is weighed and placed on the standard diet. After 4 days thestandard diet is replaced with the treatment or high fat diet, (orcontrol diet for the control group). On days 5 and 6, urine samples fromthe rats at 24 hours (+/−30 minutes) is collected and analyzed. The testrats are again weighed, and any weight loss or gain is calculated. Anyremaining food is also weighed to calculate the amount of food consumedper day. A change in phosphorus excretion relative to baseline andcellulose negative control may be calculated. Percentage reduction ofurinary phosphorous is determined by the following equation:

% Reduction of Urinary Phosphorous=[(urinary phosphorous of negativecontrol(mg/day)−urinary phosphorous of experimental(mg/day))/urinaryphosphorous of negative control(mg/day)]×100.

In Vitro Phosphate Binding (Mmol/g)

Two samples per polymer are weighed into plastic bottles after havingadjusted the weight of the polymer for the loss on drying of eachsample. A 10 mM phosphate buffer solution containing 10 mM KH₂PO₄, 100mM N,N-bis[2-hydroxyethyl]-2-aminoethanesulfonic acid, 80 mM NaCl, 15 mMglycochenodeoxycholic acid (GCDC), and 15 mM oleic acid (pH adjusted to7.0 with 1 N NaOH) is prepared and well mixed. Aliquots of the 10 mMphosphate buffer solution is transferred into each of the two samplebottles. The solutions are well mixed and then placed into an orbitalshaker at 37° C. for 1 hour. The polymer is allowed to settle prior toremoving a sample aliquot from each solution. The sample aliquot isfiltered into a small vial using a disposable syringe and syringefilter. The filtered sample is diluted 1-to-10 with DI water. Theshaking is continued for a further 4 hours (total of 5 hours) and thesampling procedure is repeated. Phosphate standards are prepared from a10 mM phosphate standard stock solution and diluted appropriately toprovide standards in the range of 0.3 to 1.0 mM. Both the standards andsamples are analyzed by ion chromatography. A standard curve is set upand the unbound phosphate (mM) for each test solution is calculated.Bound phosphate is determined by the following equation:

Bound Phosphate(mmol/g)=[(10−Unbound PO₄)×Vol.×1000]/MassP; whereinVol.=volume of test solution(L); MassP=LOD adjusted mass of polymer(mg).

In-Process Swelling Ratio (mL/g)

The in-process swelling ratio (SR) is determined by the followingequation:

SR=(weight of wet gel(g)−weight of dry polymer(g))/weight of drypolymer(g).

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope

1-100. (canceled)
 101. A pharmaceutical composition comprising, a) anamide compound represented by the following Formula III:

 wherein R₃ is independently represented by the following Formula II:

 wherein p, q and r independently represent an integer from 0-2; R₄independently represents

wherein m independently represents an integer from 1-20: R₅independently represents a hydrogen radical; a substituted orun-substituted alkyl radical; a substituted or un-substituted arylradical; or R₅ and a neighboring R₅ together represent a link or linkscomprising a residue of a crosslinking agent, a substituted orun-substituted alicyclic radical, a substituted or un-substitutedaromatic radical, or a substituted or un-substituted heterocyclicradical; or R₅ represents a link with another compound; b) acrosslinking agent or residue thereof; and c) a pharmaceuticallyacceptable excipient.
 102. A pharmaceutical composition comprising a) anamide compound represented by the following Formula V:

 wherein R₃ is independently represented by the following Formula II:

wherein p, q and r independently represent an integer from 0-2; R₄independently represents

 wherein m independently represents an integer from 1-20; R₅independently represents a hydrogen radical; a substituted orun-substituted alkyl radical; a substituted or un-substituted arylradical; or R₅ and a neighboring R₅ together represent a link or linkscomprising a residue of a crosslinking agent, a substituted orun-substituted alicyclic radical, a substituted or un-substitutedaromatic radical, or a substituted or un-substituted heterocyclicradical; or R₅ represents a link with another compound; b) acrosslinking agent or residue thereof; and c) a pharmaceuticallyacceptable excipient.
 103. A pharmaceutical composition comprising a) anamide compound represented by the following Formula VI:

b) a crosslinking agent or residue thereof; and c) a pharmaceuticallyacceptable excipient.